WO2017068043A1

WO2017068043A1 - Crosslinked serum albumin containing hyaluronic acid, for the treatment of facet joint diseases

Info

Publication number: WO2017068043A1
Application number: PCT/EP2016/075233
Authority: WO
Inventors: Helmut Wurst; Christoph Gaissmaier; Nils CLAUSEN
Original assignee: Tetec Tissue Engineering Technologies Ag
Priority date: 2015-10-21
Filing date: 2016-10-20
Publication date: 2017-04-27
Also published as: US20180311376A1; CA3002296A1; DE102015220583A1; EP3364948A1; JP2018536642A

Abstract

The invention relates to medical compositions, a medical hydrogel, a medical kit, and a multi-chamber discharge device for use in the prevention and/or treatment of a disease of the facet joints and/or in the replacement and/or regeneration of facet joint cartilage.

Description

NETWORKED SERUM ALBUMIN CONTAINING HYALURONIC ACID FOR THE TREATMENT OF

FACET JOINT DISEASES

AREA OF APPLICATION AND PRIOR ART

The invention relates to medical compositions, a medical hydrogel and a medical kit for use in the prevention and / or treatment, in particular symptomatic treatment, a disease of the facet joints and / or for use in replacement and / or in the regeneration of articular cartilage.

During normal aging or excessive stress, the spine wears off. As part of these changes, the so-called facet joints (intervertebral joints) are also heavily loaded.

The facet joints are small, plane and paired joints, which connect the dorsal processes of adjacent vertebral bodies and thus guarantee the mobility of the spine. The articular surfaces have a cartilaginous sliding layer over which the movement takes place. The joints are each surrounded by a joint capsule, in which, in addition to the vessels necessary for the blood supply, nerves for the perception of the pain also seep in.

Like any joint, the facet joint also shows degenerative changes throughout life. Normally, the facet joints have to bear only a small pressure load. The most common cause of a degenerative change in the facet joints is an increase in the size of the disc space due to wear of the intervertebral discs, herniated discs or surgical removal of the intervertebral discs. If the disc height drops only a few millimeters, the pressure load on the facet joints already increases many times over. The increased pressure causes increasing cartilage abrasion. Increasing cartilage abrasion is associated with a gradual loss of cartilage structure, which eventually manifests as manifest osteoarthritis.

A facet joint osteoarthritis is perceived by those affected as a strong back pain. The first pain usually occurs in the morning immediately after getting up, when the spine has to carry the body weight again and thereby something falls together. The worn cartilage points glide over each other, which is expressed by the pain. To make matters worse, the damaged joints are known as osteo- show phytäre reactions. This means that the facet joints, due to progressive degeneration, tend to build and build new but redundant bones. This can lead to an (additional) constriction of the nerve outlet holes of the spinal column, so that pressure on the constricted nerve produces a radiating pain symptomatology. Therefore, in addition to the typical back pain, leg pain can also occur in facet joint osteoarthritis.

The treatment of facet joint osteoarthritis covers essentially the entire spectrum of conservative options, including physical therapy. In addition, if possible, a causal therapy should be sought. In the majority of cases, however, this is not possible, since the degenerative changes, for example, the wear of the intervertebral disc elsewhere, have progressed too far, but also the osteoarthritis of the facet joints no longer allows freedom from pain. In these cases, symptomatic therapy is indicated.

A symptomatic therapeutic approach consists for example in the so-called facet joint infiltration (or in short: facet infiltration). This is a microinvasive pain therapy in which locally effective drugs are injected into the facet joints. The goal is a reduction in pain or a decrease in inflammation. The procedure is performed under imaging control (eg, computer or magnetic resonance imaging) because a blind injection misses the facet joints, and especially their joint capsules. As a rule, a local anesthetic is injected in combination with an anti-inflammatory drug, for example a cortisone preparation.

Furthermore, chondroprotective hyaluronic acid preparations are also used in the context of facet joint infiltration.

The disadvantage, however, is that a rapid diffusion of the injected drugs or drugs from the treated facet joints and depending on the drug or drug - for example, in the case of hyaluronic acid - a relatively rapid absorption takes place. Overall, this leads to a rapid loss of active ingredient in the facet joints. Therefore, as a rule, only temporary symptom reductions can be achieved among those affected. In order to achieve a clinically significant symptom reduction, multiple injections are usually required. TASK AND SOLUTION

It is therefore an object of the invention to provide a medical composition, a medical hydrogel as well as a medical kit, which is a therapy improved over the prior art, i. Prevention and / or treatment of facet joint diseases and defects.

This object is achieved by a medical composition according to independent claim 1 and by a medical hydrogel according to independent claim 18. Preferred embodiments are defined in the dependent claims. The wording of all claims is hereby incorporated by express reference into the content of the description.

In addition, further objects are disclosed in the description, which solve the object underlying the invention.

According to a first aspect, the invention relates to a medical, i. a composition which can be used in the field of medicine for use in the prevention (prophylaxis) and / or for use in the treatment, in particular symptomatic treatment, a disease of the facet joints (facet joint disease), in particular in humans or animals, and / or a medical composition for use in replacement and / or for use in the regeneration of articular cartilage, particularly human (human) or animal articular cartilage.

The composition is characterized in particular by having a crosslinkable protein.

Preferably, the composition, in particular the protein, can be converted by means of a crosslinking agent, in particular a chemical crosslinking agent, into a hydrogel-forming material or hydrogel. In other words, the composition, in particular the protein, is preferably characterized in that the composition, in particular the protein, can be crosslinked to form a hydrogel-forming material or hydrogel.

For the purposes of the present invention, the term "facet joints" is intended to mean at least one facet joint, that is to say a facet joint or a multiplicity of facet joints, such as, for example, two, three, four, etc. facet joints. For the purposes of the present invention, the expression "disease of the facet joints" or "facet joint disease" is intended to mean a physical, in particular functional and / or morphological, change of the facet joints which, in comparison with the full physiological capacity (in a healthy person and / or a healthy animal) is a deterioration.

For the purposes of the present invention, the term "animal" refers to animals, preferably vertebrates, except humans.For this, for example, the term "animal articular cartilage" in the context of the present invention refers to all animal articular cartilages, but excluding human articular cartilage.

For the purposes of the present invention, the term "crosslinkable protein" is intended to mean a protein which, owing to its chemical nature, in particular due to suitable functionalization and / or derivatization, can be crosslinked with the aid of a crosslinking agent, in particular a chemical crosslinking agent In particular, hydrogen bonding, ionic bonding, and / or covalent bonds between the protein and the crosslinking agent are preferred. Crosslinking of the protein preferably relies on covalent bonds between the protein and the crosslinking agent.

For the purposes of the present invention, the term "crosslinking agent" is to be understood as meaning a compound which has at least two reactive groups, in particular only two reactive groups The reactive groups are preferably, as will be explained in more detail below, thiol groups , that is SH groups.

For the purposes of the present invention, the term "hydrogel" is intended to mean a water-containing, three-dimensional, polymeric network (or a water-containing, three-dimensional, polymeric matrix.) The formation of the network (or of the matrix) is preferably based on the formation of chemical and / or physical bonds or linkages between starting components (such as, in particular, a crosslinkable protein and a crosslinking agent) which are used to prepare the network (or the matrix) .The chemical bonds may be covalent and / or non-covalent. Preferably, the bonds are covalent bonds, at least predominantly covalent bonds The non-covalent bonds can be selected from the group comprising ionic bonds, hydrogen bonds bonds, dipole-dipole interactions, van der Waals forces, and a combination of two or more of said non-covalent bonds.

The invention is based on the surprising finding that a crosslinkable protein in the presence of active ingredients, such as chondroprotective agents, anti-inflammatory drugs, local anesthetics or the like, can be crosslinked to a hydrogel-forming material or hydrogel, which causes a delayed (retarded) release of the active ingredients. If such a hydrogel-forming material or hydrogel is produced in diseased facet joints or administered to diseased facet joints, the loss of active ingredient known from the prior art (by diffusion and, in particular, absorption) can be delayed. Due to the described retarding effect, active ingredients contained in the hydrogel-forming material or hydrogel remain localized over a longer period of time in the facet joints, in particular in their joint capsules, or at least in the vicinity of the facet joints. The active ingredients can thus develop their desired effect over a longer period of time. As a result, compared to generic treatment approaches significantly more effective and sustainable treatment of facet joint disorders is possible. At the same time, the hydrogel-forming material or hydrogel can serve as a replacement structure for diseased articular cartilage and / or as a structure for reconstructions, that is to say neogenesis, of facet joint cartilage.

By a longer active ingredient localization in the facet joints, moreover, the number of treatment cycles necessary for a perceptible treatment success, for example the number of injections in the case of facet joint infiltration, can be significantly reduced. On the one hand, this improves the life situation of those affected. On the other hand, this treatment costs can be saved to a significant extent.

It is furthermore advantageous that the hydrogel-forming material or hydrogel can be distinguished by antineurotrophic, anti-osteogenic and / or antiadhesive properties, which additionally improve the possibilities for the prevention and / or treatment of facet joint disorders as well as for the replacement and / or regeneration of articular cartilage to let.

Another advantage is that the hydrogel-forming material or hydrogel acts as an infiltration barrier for inflammatory cells and thus exerts an anti-inflammatory effect.

Finally, it is advantageous that the composition, in particular the protein, can be readily combined with active ingredients, which will be discussed in more detail below. Although crosslinkable proteins have already been described in DE 10 2008 008 071 A1 and DE 10 2009 051 575 A1 in general in connection with the treatment of cartilage and intervertebral disc defects as well as arthritis. However, their use for the prevention and / or treatment, in particular symptomatic treatment, of facet joint diseases and for the replacement and / or regeneration of articular cartilage was not known.

In a preferred embodiment, the formation of the hydrogel-forming material or hydrogel is based on a Michael addition between the protein and the crosslinking agent, the protein preferably reacting as a Michael acceptor and the crosslinking agent as a Michael donor.

In another embodiment, the facet joints are lumbar, thoracic and / or cervical facet joints. Preferably, the facet joints are lumbar facet joints.

In another embodiment, the articular cartilage is lumbar, thoracic and / or cervical articular cartilage. Preferably, the articular cartilage is lumbar facet joint cartilage.

The term "lumbar" in the sense of the present invention means "belonging to the lumbar region". The term "thoracic" in the sense of the present invention means "belonging to the chest (thorax)". The term "cervical" in the sense of the present invention means "belonging to the neck".

In another embodiment, the disease of the facet joints is a degenerative disease of the facet joints, that is, a degenerative facet joint disease.

For the purposes of the present invention, the term "degenerative disease of the facet joints" or "degenerative facet joint disease" is to be understood as meaning a facet joint disease which is based on a functional and / or morphological change in the facet joints which, in comparison to the full physiological capacity (in US Pat a healthy person and / or animal) constitute a deterioration. For the purposes of the present invention, the cause of a degenerative facet joint disease can be, in particular, advanced age, an excessive amount of stress (for example increased body weight), congenital or traumatic causes such as deformities of the facet joints, bone deformities due to bone diseases (such as osteoporosis and / or other disorders, such as arthritis) or (previous) injuries to the facet joints. A characteristic feature of a degenerative facet joint disease in the sense of the present invention is in particular a loss of competence of the facet joints, in particular of the affected articular cartilage.

In a particularly preferred embodiment, the disease, in particular degenerative disease, of the facet joints is osteoarthritis of the facet joints, that is to say a facet joint osteoarthritis.

Arthrosis may basically be primary or idiopathic osteoarthritis, secondary or symptomatic osteoarthritis or activated osteoarthritis.

For the purposes of the present invention, the term "primary osteoarthritis or idiopathic arthrosis" is understood to be osteoarthritis which is caused by a mismatch between the load and the load bearing capacity of the articular cartilage (obesity, overloading, etc.), congenital misalignments or joint dysplasias In the context of the present invention, the term "secondary or symptomatic arthrosis" should be understood as an arthritis which is traumatic (joint misalignments after trauma, joint injuries after trauma, etc.), metabolically (tissue / bone damage in the case of deficient circulation, diabetes mellitus, alcoholism, inflammation, etc.) or medically (for example by gyrase inhibitors). For the purposes of the present invention, the term "activated osteoarthritis" should be understood as an osteoarthritis which accompanies inflammation ("inflamed" arthrosis).

According to a particularly preferred embodiment, the disease of the facet joints is a secondary or symptomatic arthrosis of the facet joints.

In another embodiment, the disease of the facet joints is an inflammatory disease of the facet joints, that is, an inflammatory facet joint disease.

Preferably, the disease, in particular inflammatory disease, of the facet joints is an arthritis of the facet joints, that is to say a facet joint arthritis.

In principle, the composition may be prepared for conversion to the hydrogel-forming material or hydrogel before, during or after its administration. In particular, the composition may be prepared for in situ conversion into the hydrogel-forming material or hydrogel. In other words, according to the invention it can be provided, in particular, that the composition is converted into a hydrogel-forming material or hydrogel only in situ, ie directly on the site to be treated.

The composition is in a further embodiment in sprayable form.

Preferably, the composition is in injectable form.

In principle, the composition may be prepared for surgical administration. In other words, the composition can be surgically used.

However, in a preferred embodiment, the composition is adapted for microinvasive administration. In other words, however, it is preferred according to the invention if the composition is used or used microinvasively.

The composition is, according to a particularly preferred embodiment, for facet joint infiltration, i. for infiltration, preferably injection, prepared in the facet joints. In other words, the composition is particularly preferred for facet joint infiltration, i. for infiltration, preferably injection, used in the facet joints or administered in the facet joints, preferably injected.

Especially preferred is when the composition is for intra-articular facet joint infiltration, i. for infiltration, preferably injection, into the articular capsules of the facet joints. In other words, it is particularly preferred if the composition is for intra-articular facet joint infiltration, i. for infiltration, preferably injection, used in the joint capsules of the facet joints or administered in the joint capsules of the facet joints, preferably injected.

Alternatively or in combination, the composition may be prepared for peri-articular facet joint infiltration, ie for infiltration, preferably injection, in the vicinity of the facet joints or around the facet joints (outside of the joint capsules). In other words, according to the invention, it can alternatively or additionally be provided that the composition is used for peri-articular facet joint infiltration or is administered, preferably injected, in the vicinity of the facet joints or around the facet joints (outside the joint capsules). The medical composition in another embodiment is an acellular composition, that is, a composition that is free of cells.

In a further embodiment, the protein provided according to the invention is a hydrophilic, in particular water-soluble, protein.

In other embodiments, the protein is a naturally occurring protein, especially a blood serum protein.

In an alternative embodiment, the protein is an artificially produced protein. For example, the protein may be a chemically synthesized or recombinantly produced protein.

In principle, the protein can be of human or animal origin. For example, the protein may be a protein of bovine origin (bovine), porcine origin (porcine), equine origin (horse), ovine origin (sheep), caprine origin (goat) or leporid origin (rabbit). However, according to the invention it is preferred if the protein is a human protein.

Furthermore, the protein may basically be allogeneic, autologous or xenogenic origin. According to the invention it is preferred if the protein is an allogeneic protein.

In a preferred embodiment, the protein is a functionalized protein.

For the purposes of the present invention, the term "functionalized protein" is to be understood as meaning a protein which, for example by adding functional groups, has a function which it normally does not possess.

In a preferred embodiment, the protein is functionalized by functional groups, in particular thiol-reactive groups.

For the purposes of the present invention, the term "thiol-reactive groups" is to be understood as meaning functional groups which are capable of reacting with thiol and / or thiolate groups of another compound, preferably a crosslinking agent. The functional groups may, in a further embodiment, be selected from the group consisting of maleimide groups, vinylsulfone groups, acrylate groups, alkyl halide groups, azirole groups, pyridyl groups, thionitrobenzoic acid groups, arylating groups and combinations of two or more of said functional groups.

Preferably, the protein is a maleimide-functionalized protein, in particular maleimide-functionalized serum protein, preferably of human origin.

In a further embodiment, thiol groups, preferably all thiol groups, of the protein are blocked. The blocking of the thiol groups is preferably based on a reaction of the protein with a maleimide compound, in particular with N-maleoyl-β-alanine (3-maleimido-propionic acid) or 3-maleimido-propionic acid N-hydroxysuccinimide ester.

In another embodiment, primary amino groups of the protein are blocked. Preferably, a significant proportion of the primary amino groups, in particular 10% to 70% of the primary amino groups, of the protein is blocked. The blocking is preferably based on a reaction of the protein with a maleimide-functionalized active ester, in particular with 3-maleimido-propionic acid N-hydroxysuccinimide ester.

For the purposes of the present invention, the term "active ester" is understood to mean an ester which has an increased acylation potential due to a particularly pronounced electron-attracting effect of the alcohol moiety.

In a further embodiment, the protein is prepared or preparable from an unfunctionalized protein by reaction with N-maleoyl-.beta.-alanine and subsequent reaction with 3-maleimido-propionic acid N-hydroxysuccinimide ester.

In a further embodiment, the protein has a fraction of from 0.3% by weight to 20% by weight, in particular from 0.4% by weight to 5% by weight, preferably from 0.5% by weight to 2% by weight, based on the total weight of the composition.

In another embodiment, the protein is selected from the group consisting of crosslinkable albumin, crosslinkable serum proteins, derivatives thereof and mixtures of two or more of said proteins. The term "derivative" or "derivatives" is intended in the context of the present invention to mean a protein which is produced starting from an unfunctionalized protein by derivatization. Examples of possible derivatization include the covalent attachment of functional groups and / or biological factors, the change in the state of charge and / or polarization, and / or the change in the protein structure.

In a particularly preferred embodiment, the protein is a maleimide-functionalized albumin, especially maleimide-functionalized serum albumin, preferably of human origin.

In a further embodiment, the composition further comprises at least one active ingredient.

The active ingredient is preferably selected from the group consisting of or consisting of chondroprotective, antiphlogistic, analgesic, antibiotic, local anesthetic, cytostatic, differentiation factor, modulation factor, immunosuppressant, immunostimulating agent, apoptosis-inducing agent and mixtures of two or more of said agents.

For the purposes of the present invention, the term "chondroprotective agent" is to be understood to mean a cartilage-protecting compound, the cartilage-protecting action generally being based on inhibiting cartilage-degrading substances and thus reducing the loss of protective cartilage.

The chondroprotective agent may in particular be selected from the group comprising or consisting of hyaluronic acid, chondroitin sulfate, glucosamine sulfate, oxaceprol, antioxidants (such as vitamin E), ademethionine (S-adenosylmethionine SAN), derivatives of said chondroprotective agents and mixtures of two or more of said chondroprotective agents.

Preferably, the chondroprotective agent is hyaluronic acid. The hyaluronic acid can be uncrosslinked or crosslinked.

In a further embodiment, the chondroprotective agent has a proportion of 0.1% by weight to 5% by weight, in particular 0.2% by weight to 2% by weight, preferably 0.3% by weight to 1% by weight, based on the total weight of the composition. In a further embodiment, the medical composition further comprises a topical anesthetic, that is, a topical anesthetic agent selected from the group consisting of or consisting of lidocaine, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, editocaine, dyclonine, procaine, benzocaine , 2-chloro-procaine, oxybuprocaine, tetracaine, fomocaine, derivatives of said local anesthetics and mixtures of two or more of said local anesthetics.

In a further embodiment, the local anesthetic has a proportion of 0.05% by weight to 15% by weight, in particular 0.1% by weight to 10% by weight, preferably 0.2% by weight to 5% by weight, based on the total weight of the composition.

The above-mentioned anti-inflammatory (antiinflammatory) agent may be selected from the group consisting of or consisting of steroidal anti-inflammatory drug, non-steroidal anti-inflammatory drug, anti-inflammatory drug and mixtures of two or more of said anti-inflammatory drugs.

For example, the antiphlogistic agent may be selected from the group consisting of or consisting of ibuprofen, acetylsalicylic acid, diclofenac, indomethacin, phenylbutazone, dexamethasone, hydrocortisone, prednisolone, prednisone, betamethasone, triamcinolone, essential oils or extracts, in particular from camomile and / or arnica flowers , Derivatives of said antiphlogistics (such as betamethasone acetate, triamcinolone acetonide, triamcinolone hexacetonide and / or methylprednisolone) and mixtures of two or more of said antiphlogistics.

In a further embodiment, the antiphlogistic agent has a proportion of 0.02% by weight to 15% by weight, in particular 0.05% by weight to 10% by weight, preferably 0.1% by weight to 5% by weight, based on the total weight of the composition.

In another embodiment, the composition further comprises a crosslinking agent. Preferably, the crosslinking agent is spatially separated from the crosslinkable protein. In this way, premature crosslinking of the protein can be prevented. In other words, according to another embodiment, the composition comprises, separately from one another, a crosslinkable protein and a crosslinking agent. In this embodiment, the composition may be present in particular as a kit. With regard to the crosslinkable protein, reference is made in full to the previous description. The crosslinking agent may in principle be a homomultifunctional, in particular homobifunctional, or heteromultifunctional, in particular heterobifunctional, crosslinking agent. Preferably, the crosslinking agent is a homobifunctional crosslinking agent.

The crosslinking agent has thiol groups (SH groups) in another embodiment.

In particular, the crosslinking agent may be a thiol-functionalized or modified crosslinking agent.

Furthermore, the crosslinking agent may be a polymer, in particular a thiol-functionalized or modified polymer.

For example, the crosslinking agent may be selected from the group consisting of or consisting of dithio-polyethylene glycol (dithio-PEG), SH-modified hyaluronic acid, SH-modified dextran, SH-modified polyvinyl alcohol, SH-modified polyvinylpyrrolidone and mixtures of two or more of said crosslinking agents ,

According to a particularly preferred embodiment, the crosslinking agent is a thiol-functionalized or modified polymer, in particular dithio-polyethylene glycol (dithio-PEG).

In a particularly preferred embodiment, the crosslinkable protein is maleimide-functionalized albumin, especially maleimide-functionalized serum albumin, and the crosslinking agent is dithio-polyethylene glycol (dithio-PEG). In this case, the crosslinking reaction relies on a Michael addition between the maleimide groups of the albumin (Michael acceptor) and the thiol groups of the dithio-polyethylene glycol (Michael donor).

In a further embodiment, the composition further comprises salts and / or saccharides. The salts may in particular be sodium chloride and / or buffer salts, preferably a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate. The saccharides may in particular be trehalose.

In a further embodiment, the medical composition further comprises a contrast agent. The use of a contrast agent allows a particular advantage treatment under imaging control, for example by means of computer or magnetic resonance tomography.

The contrast agent may be selected, for example, from the group comprising or consisting of iodine-containing or iodine-substituted contrast agent, barium sulfate and mixtures of two or more of said contrast agents.

In an embodiment which is advantageous from a storage standpoint, the composition, in particular the crosslinkable protein and / or an optionally additionally present crosslinking agent, is in solid form, in particular as lyophilisate.

In a further embodiment, the medicinal composition, in particular the crosslinkable protein and / or an optionally additionally present crosslinking agent, is in the form of an aqueous liquid, in particular in the form of a suspension or solution, preferably a solution.

In a second aspect, the invention relates to a medical hydrogel-forming material or medical hydrogel, i. a hydrogel-forming material or hydrogel which can be used in the field of medicine, for use in the prevention (prophylaxis) and / or for use in the treatment, in particular symptomatic treatment, of a disease of the facet joints (facet joint disease), in particular in humans or animals, and / or a medical hydrogel-forming material or hydrogel for use in replacement and / or for use in the regeneration of articular cartilage, in particular human (human) or animal articular cartilage.

The hydrogel-forming material or hydrogel can be obtained or prepared by mixing a crosslinkable protein and a crosslinking agent.

By mixing, a crosslinking reaction between the protein and the crosslinking agent takes place to form a hydrogel-forming material or hydrogel.

The hydrogel-forming material or hydrogel can be obtained or prepared in particular by mixing an aqueous liquid, in particular aqueous suspension or aqueous solution, containing a crosslinkable protein, and an aqueous liquid, in particular aqueous suspension or aqueous solution, containing a crosslinking agent. In principle, the hydrogel-forming material or hydrogel can be prepared for surgical administration. In other words, it can be provided according to the invention that the hydrogel-forming material or hydrogel is used or used surgically.

In a preferred embodiment, however, the hydrogel-forming material or hydrogel is prepared for microinvasive administration. In other words, it is preferred according to the invention if the hydrogel-forming material or hydrogel is used or administered in a microinvasive manner.

In a particularly preferred embodiment, the hydrogel-forming material or hydrogel is for facet joint infiltration, i. for infiltration, preferably injection, prepared in the facet joints. In other words, it is particularly preferred according to the invention if the hydrogel-forming material or hydrogel is used for facet joint infiltration or is administered into the facet joints, preferably injected.

It is particularly preferred for the hydrogel-forming material or hydrogel to be used for intra-articular facet gene infiltration, i. for infiltration, preferably injection, into the articular capsules of the facet joints. In other words, it is particularly preferred if the hydrogel-forming material or hydrogel is used for intra-articular facet joint infiltration or administered into the joint capsules of the facet joints, preferably injected.

Alternatively or in combination, the hydrogel-forming material or hydrogel may be used for peri-articular facet joint infiltration, i. for infiltration, preferably injection, near the facet joints or around the facet joints (outside the joint capsules). In other words, the hydrogel-forming material or hydrogel can alternatively or additionally be used for peri-articular facet joint infiltration or be administered in the vicinity of the facet joints or around the facet joints (outside the joint capsules), preferably injected.

With regard to further features and advantages of the hydrogel-forming material or hydrogel, in particular of the crosslinkable protein and of the crosslinking agent, reference is made to the complete description to avoid repetition. The remarks made in the context of the previous description, ie in the context of the first aspect of the invention, with regard to the crosslinkable protein and the crosslinking agent also apply to the hydrogel-forming material or hydrogel according to the invention. According to a third aspect, the invention relates to a medical, ie a usable in the field of medicine, kit for use in the prevention (prophylaxis) and / or for use in the treatment, in particular symptomatic treatment, a disease of the facet joints (facet joint disease), in particular in humans or animals, and / or a medical kit for use in replacement and / or for use in the regeneration of articular cartilage, in particular human (human) or animal articular cartilage.

The kit comprises, spatially separated from each other, the following components: a) a crosslinkable protein and b) a crosslinking agent.

In principle, the kit may be prepared for surgical administration. In other words, it may be provided according to the invention that the kit is used surgically or used.

However, in a preferred embodiment, the kit is adapted for microinvasive administration. In other words, it is preferred according to the invention if the kit is used or used microinvasively.

In a particularly preferred embodiment, the kit is for facet joint infiltration, i. for infiltration, preferably injection, prepared in the facet joints. In other words, it is particularly preferred according to the invention if the kit is used for facet joint infiltration or if the kit components a) and b) are administered into the facet joints, preferably injected.

It is particularly preferred if the kit for intraarticular facet gene infiltration, i. for infiltration, preferably injection, into the articular capsules of the facet joints. In other words, it is particularly preferred if the kit is used for intra-articular facet joint infiltration or the kit components a) and b) are administered, preferably injected, into the joint capsules of the facet joints.

Alternatively or in combination, the kit may be adapted for peri-articular facet joint infiltration, ie for infiltration, preferably injection, near the facet joints or around the facet joints (outside the joint capsules). In other words Alternatively or additionally, the kit may be used for peri-articular facet joint infiltration or the kit components a) and b) may be administered, preferably injected, in the vicinity of the facet joints or around the facet joints (outside the joint capsules).

In an expedient embodiment, the kit components a) and b) are each contained in a separate container. In other words, according to an expedient embodiment, the kit according to the invention is a kit which has a first container containing a crosslinkable protein and a second container containing a crosslinking agent. The containers may each be, for example, a cartridge, a cartridge, a syringe container, in particular a syringe barrel, or a chamber of a multi-chamber discharge device, in particular a two-chamber discharge device.

In a further embodiment, the kit component a) and / or the kit component b) may further comprise an active ingredient and / or a contrast agent. With regard to a suitable active ingredient and / or contrast agent, reference is made in full to the previous description. The remarks made in the context of the previous description with respect to possible active ingredients and contrast agents also apply to the kit component a) and / or the kit component b).

With regard to further features and advantages of the kit, in particular of the crosslinkable protein and of the crosslinking agent, reference is likewise made to the previous description in order to avoid repetitions. The statements made in the context of the previous description, in particular in the context of the first aspect of the invention, with respect to the crosslinkable protein and the crosslinking agent also apply to the kit according to the invention.

According to a fourth aspect, the invention relates to a multi-chamber discharge device, in particular a two-chamber discharge device, for use in prevention (prophylaxis) and / or for use in the treatment, in particular symptomatic treatment, of facet joint disease (facet joint disease), in particular in humans or animals, and / or a Mehrkammeraustragsvorrichtung, in particular Zweikammeraustragsvornchtung, for use in replacement and / or for use in the regeneration of articular articular cartilage, in particular human (human) or animal facet joint cartilage.

The multi-chamber discharge device has a first chamber containing a crosslinkable protein and a second chamber containing a crosslinking agent. In a further embodiment, the multi-chamber discharge device has a mixing device. In the mixing device, a mixing of the protein and the crosslinking agent takes place, for example by means of a static mixer, before the mixture is discharged via a suitable discharge opening.

In a further embodiment, the first chamber and / or the second chamber may further comprise an active agent and / or a contrast agent. With regard to a suitable active ingredient and / or contrast agent, reference is made in full to the previous description. The statements made in the context of the previous description with respect to possible active ingredients and contrast agents also apply to the multi-chamber discharge device according to the invention.

With respect to further features and advantages of the multi-chamber discharge device, in particular the crosslinkable protein and the crosslinking agent, reference is likewise made to the previous description to avoid repetition. The statements made in the context of the previous description, in particular in the context of the first aspect of the invention, with respect to the crosslinkable protein and the crosslinking agent also apply to the multichamber discharge device according to the invention.

The invention according to a fifth aspect relates to another medical, i. a usable in the field of medicine, composition for use in the prevention (prophylaxis) and / or for use in the treatment, in particular symptomatic treatment, a disease of the facet joints (facet joint disease), in particular in humans or animals, and / or another medical Composition for use in replacement and / or for use in the regeneration of articular cartilage, in particular human (human) or animal articular cartilage.

The further medical composition is characterized in particular by having a crosslinking agent.

With regard to further features and advantages of the further medical composition, in particular of the crosslinking agent and of possible active ingredients and / or contrast agents, reference is likewise made to the previous description to avoid repetition. The remarks made in the context of the previous description in relation to the medicinal composition described so far, in particular the crosslinkable protein and possible active ingredients and / or contrast agents, as well as the crosslinking agent also apply to the further medical composition. Finally, the invention relates to a method for the prevention (prophylaxis) and / or treatment of a facet joint disease and / or for the replacement and / or regeneration of articular cartilage, wherein a crosslinkable protein is administered in combination with a crosslinking agent in facet joints of a human or animal patient ,

In principle, the administration of the crosslinkable protein and the crosslinking agent can be performed surgically or minimally invasively.

However, in a preferred embodiment, the administration of the crosslinkable protein and the crosslinking agent is by injection into the facet joints.

In a particularly preferred embodiment, the administration of the crosslinkable protein and the crosslinking agent is effected by an intra-articular and / or periarticular, preferably intra-articular, facet joint infiltration.

With regard to further features and advantages of the process, in particular of the crosslinkable protein and of the crosslinking agent, reference is likewise made to the previous description in order to avoid repetitions. The statements made in the context of the previous description in relation to the crosslinkable protein and the crosslinking agent also apply to the process according to the invention.

Further features and advantages of the invention will become apparent from the following description of preferred embodiments in the form of examples. In this case, individual features can be implemented individually or in combination with each other. The preferred embodiments are merely for further explanation and understanding of the invention without limiting it thereto.

example part

1 . Preparation of maleimide-functionalized serum albumin of bovine origin.

250 mg of human, rabbit, bovine or ovine serum albumin (Sigma-Aldrich) were dissolved in 5 ml of 1 M sodium borate (pH 8.2).

Furthermore, 106 mg of 3-maleimido-propionic acid N-hydroxysuccinimide ester (SMP, Obiter Research, Urbana, IL, USA) were dissolved in 950 μM dimethylformamide (DMF). Insoluble material was separated by centrifugation. Subsequently, 500 μΙ of the supernatant was added to the Given albumin solution. It was then incubated for a further 60 min at room temperature. Thereafter, 500 μΙ 3 M sodium acetate (pH 4.7) were added and dialysed three times against 1 l PBS on ice. The dialysate was then concentrated by ultrafiltration (YM-3 membrane, millipore) to a volume of 3.5 ml, filter sterilized and stored at -80 ° C.

The functionalized serum albumin can be crosslinked in the presence of hyaluronic acid by addition of SH crosslinkers. Particularly suitable is the crosslinker bis-thio-polyethylene glycol, which carries a thiol group at both ends. Bis-thio-PEG is commercially available. The crosslinker with a molecular weight of 10,000 g / mol was used. The best gelation was achieved when the SH groups of bis-thio-PEG and the iminimide groups of the albumin were present in equimolar concentrations.

The hyaluronic acid containing gels were then tested for their ability to release hyaluronic acid. For this purpose, a hydrogel was prepared by crosslinking 3 mmol / L of maleimide groups coupled to albumin and 3 mmol / L of polyethylene glycol-coupled thiol groups, which additionally contained 1% (w / v) hyaluronic acid, with a total volume of 1 ml of phosphate-buffered (pH 7 ) isotonic saline. An area of about 2 cm ^{2 of} this hydrogel was overlaid with a volume of 1 ml of phosphate buffered isotonic saline and incubated at 37 ° C. The isotonic saline solution was replaced after three days by fresh isotonic saline solutions. The used isotonic saline solution was dialyzed against distilled water and concentrated by lyophilization.

As a reference, the same experimental setup was constructed, in which, however, unfunctionalized polyethylene glycol was used instead of the bis-thofunctionalized crosslinker.

The used salt solutions were analyzed with a gel filtration chromatography system coupled with a viscosity detector.

It was observed that hyaluronic acid was released from the hydrogel significantly more slowly into the over-layered saline solution than from the uncrosslinked reference material.

Claims

claims

1 . A medicinal composition for use in the prevention and / or treatment, in particular symptomatic treatment, of a disease of the facet joints and / or for use in the replacement and / or regeneration of articular cartilage, characterized in that the composition comprises a crosslinkable protein and by means of a crosslinking agent can be converted into a hydrogel-forming material or hydrogel.

2. Medicinal composition for use according to claim 1, characterized in that the facet joints are lumbar facet joints.

3. Medicinal composition for use according to claim 1 or 2, characterized in that the disease is a degenerative disease, preferably osteoarthritis, in particular secondary or symptomatic arthrosis.

4. Medicinal composition for use according to one of the preceding claims, characterized in that the composition is prepared for facet joint infiltration, in particular intra-articular facet joint infiltration.

5. Medicinal composition for use according to one of the preceding claims, characterized in that the composition is an acellular composition.

6. Medicinal composition for use according to one of the preceding claims, characterized in that the protein is functionalized by groups, in particular thiol-reactive groups, which are preferably selected from the group comprising maleimide groups, vinylsulfone groups, acrylate groups, alkylhalide groups, azirino groups, Pyridyl groups, thionitrobenzolic acid groups, arylating groups, and combinations thereof.

7. Medicinal composition for use according to one of the preceding claims, characterized in that the protein is a maleimide-functionalized protein, in particular a maleimide-functionalized albumin, preferably a maleimide-functionalized serum albumin.

8. Medicinal composition for use according to one of the preceding claims, characterized in that the protein has a proportion of 0.3 wt .-% to 20 wt .-%, in particular 0.4 wt .-% to 5 wt .-%, preferably 0.5 wt. % to 2% by weight, based on the total weight of the composition.

9. Medicinal composition for use according to any one of the preceding claims, characterized in that the composition further comprises at least one active ingredient selected from the group comprising chondroprotectivum, antiphlogistic, analgesic, antibiotic, local anesthetic, cytostatic, differentiation factor, modulation factor, immunosuppressant , immunostimulating agent, apoptosis-inducing agent and mixtures of two or more of said agents.

10. Medicinal composition for use according to claim 9, characterized in that the chondroprotective agent is selected from the group comprising hyuronic acid, chondroitin sulfate, glucosamine sulfate, oxaceprol, vitamin E, ademethionine and mixtures of two or more of said chondroprotective agents.

1 1. Medicinal composition for use according to Claim 9 or 10, characterized in that the chondroprotective agent contains from 0.1% by weight to 5% by weight, in particular from 0.2% by weight to 2% by weight, preferably 0.3% by weight to 1 wt .-%, based on the total weight of the composition.

12. Medicinal composition for use according to claim 9, characterized in that the local anesthetic is selected from the group comprising lidocaine, mepivacaine, prilocaine, articaine, bupivacaine, ropivacaine, etidocaine, dyclonine, procaine, benzocaine, 2-chloroprocaine, oxybuprocaine, tetracaine, Fomocaine and mixtures of two or more of said local anesthetics.

13. Medicinal composition for use according to claim 9 or 12, characterized in that the local anesthetic a proportion of 0.05 wt .-% to 15 wt .-%, in particular 0.1 wt .-% to 10 wt .-%, preferably 0.2 wt. % to 5% by weight, based on the total weight of the composition.

14. Medicinal composition for use according to claim 9, characterized in that the anti-inflammatory agent is selected from the group comprising ibuprofen, acetylsalicylic acid, diclofenac, indomethacin, phenylbutazone, dexamethasone, Hydrocortisone, prednisolone, essential oils, in particular of chamomile and arnica flowers, and mixtures of two or more of said anti-inflammatory drugs.

15. Medicinal composition for use according to claim 9 or 14, characterized in that the anti-inflammatory agent in a proportion of 0.02 wt .-% to 15% by weight, in particular 0.05 wt .-% to 10 wt .-%, preferably 0.1 wt. % to 5% by weight, based on the total weight of the composition.

16. A medical composition for use according to any one of the preceding claims, characterized in that the composition further comprises at least one crosslinking agent, preferably an SH-modified crosslinking agent, wherein the crosslinking agent is spatially separate from the crosslinkable protein.

17. A medical composition according to claim 16, characterized in that the crosslinking agent is selected from the group comprising dithio-polyethylene glycol (dithio-PEG), SH-modified hyaluronic acid, SH-modified dextran, SH-modified polyvinyl alcohol, SH-modified polyvinylpyrrolidone and mixtures from two or more of said crosslinking agents.

18. Medicinal hydrogel for use in the prevention and / or treatment, in particular symptomatic treatment, of a disease of the facet joints and / or for use in replacement and / or in the regeneration of facet joint cartilage, characterized in that the hydrogel is prepared by mixing a crosslinkable gel Protein and a crosslinking agent is available.